Nanopore sequencing technology allows one to measure the ionic current generated by a molecule moving across the nanopores thereby identifying the molecule. An ionic current is a current generated by the flow of ions. In particular, nanopore sequencing enables sequencing individual nucleotide bases. Nanopore sequencing technology can also be applied to a polynucleotide or a polypeptide. Examples of polynucleotides includes, but not limited to, a double-stranded DNA, single stranded DNA, double-stranded RNA, single-stranded RNA, or DNA-RNA hybrid. For example, DNA bases from a DNA strand can be sequenced with the nanopore sequencing without any modification to that strand. The nanopore channels can be fabricated either by inserting a protein channel into a lipid membrane or by fabricating “solid-state” nanopores in a semiconductor substrate such as silicon or silicon nitride. Based on modern semiconductor fabrication technology, solid-state nanopores can enable DNA sensing at relatively low cost.
Nanopore sequencing is based on the use of nanopore sensors. A nanopore sensor has two chambers, referred to as a cis and a trans chamber that are connected by a very small channel called a nanopore. To induce the DNA being sequenced to enter the nanopore, a voltage is induced across the sensor. The chambers are filled with a buffered ionic conducting solution (e.g. KCl, CaCl2, NaCl etc.). The conducting solution and the applied voltage create an ionic current. Negatively charged DNA in the cis chamber starts moving towards the trans side. As it traverses the nanopore the ionic current, which is in the range of tens to hundreds of picoAmperes, is modulated by the DNA bases. The DNA base modulated current can be sensed and analyzed to implement an electrical DNA sequencing method.
Nanopore sequencing currents are in the tens to hundreds of picoAmperes, and therefore practical, commercial nanopore sequencing systems require very low noise at very high gains. More cost-effective and space-effective designs are desirable. Submicron CMOS technology makes it theoretically possible to miniaturize multiple nanopore measuring instrumentation by making it on a semiconductor substrate.
Accurately measuring ultra-low current variations requires patch-clamps with very high gain. Patch clamp amplifiers usually take the form of differential op-amp transimpedance amplifiers that use either resistive or capacitive feedback. A transimpedance amplifier is one that converts current to voltage.
FIG. 5 presents a resistive feedback transimpedance amplifier 500. The amplifier 500 of FIG. 5 has two main components: a very high gain amplifier network and a compensation network. In FIG. 5 the compensation network includes feedback resistor RF 507, while the high gain amplifier network includes Op Amp 501, Op Amp 502, and four gain control resistors labeled R1 508 and R2 510. See B. Sakmann and E. Neher, “Single-channel recording,” Plenum Press, New York, 1995.
In FIG. 5, an enabling/disabling command voltage VCMD 504 is applied to the non-inverting input 506 of Op Amp 501, while the potential across a nanopore sensor, which represents an ionic current 503, is applied to the inverting input 505 of Op Amp 501. The ionic current 503 is amplified by the gain of the high gain of the amplifier 500. The gain of the resistive feedback transimpedance amplifier is thus:
  Gain  =            R      F        ×                  R        2                    R                  1          ⁢                                                    
In the resistive feedback transimpedance amplifiers as shown in FIG. 5, the input-referred noise current is inversely proportional to RF. See J. Kim, G. Wang, W. Dunbar and K. Pedrotti, “An integrated patch-clamp amplifier for ultra-low current measurement on solid-state nanopore device,” in Proc. IEEE Int. SoC Design Conf., pp. 424-427, November 2010.
To minimize input noise and to maximize total gain in the resistive feedback transimpedance amplifiers such as shown in FIG. 5, the resistance of feedback resistor RF 507 must be set to be as large as possible. Therefore, implementing high gain and low noise amplifiers using the resistive feedback configuration on a semiconductor chip is problematic because that high value resistances (at least tens of mega-Ohms) that are suitable for use as feedback resistors RF 507 require large chip areas. In practical applications the basic resistive feedback amplifier shown in FIG. 5 only allows about 1 to 8 amplifiers to be integrated on a single chip. If only 10 to 100 nanopore sensors are used in a given application the basic resistive feedback amplifier of FIG. 5 is acceptable. However, to maximize nanopore sequencing through-put it is highly desirable to increase the number of nanopore sensors that can operate asynchronously and in parallel. The latest sequencing device from Ion Torrect (now part of Life Technologies) has 1.2 Million addressable measurement wells (but read-length is limited by the use of enzymes for sequencing). Thus if the objective is 1 k-10 k nanopore sensors or more per device, an alternative design or an improvement to the basic resistive feedback amplifier of FIG. 5 may be recommended.
It should be noted that several pseudo-resistor techniques have been developed to reduce the required dimensions to implement large resistor values. See for example, R. R. Harrison and C. Charles, “A low-power low-noise CMOS amplifier for neural recording applications,” IEEE Journal of Solid-State Circuits, 38: 958-965, June 2003 and M. Chae, J. Kim, W. Liu, “Fully-differential self-biased bio-potential amplifier,” Electron. Lett., vol. 44, no. 24, pp. 1390-1391, November 2008. One drawback of pseudo-resistors is that pseudo-resistors require care to achieve precise resistance desired. A pseudo-resistor is implemented as the resistance between the source and drain of a FET on a die.
In view of the foregoing, a new technique for implementing amplifiers on a die would be beneficial. Such a new technique should enable high density amplifiers on the die. Preferably such techniques would be suitable for use with high through-put nanopore sequencing. Such techniques might be scaled to implement at least 2000 and hopefully at least 5,000 or 10,000 or 20,000 or 30,000 or at least 40,000 nanopore amplifiers on a single die.